Field of the Invention
The present invention relates to a new class of anti-cancer compounds and their therapeutic uses.
Background of the Invention
Despite the existence of tens of approved antiproliferation drugs, the treatment of many kinds of leukemia and other cancers is still not very successful. Thus the development of new type of compounds with anti-cancer properties is in demand.
Recently the present inventors discovered a new class of cytostatic compounds, 7-(het)aryl-7-deazaadenosines, of formula A. (See Bourderioux, A.; Nau{hacek over (s)}, P.; Hocek, M., U.S. 61/171,656 (2009), PCT/CZ2010/000050, WO2010121576 A2; Bourderioux, A.; Nau{hacek over (s)}, P.; Perlíková, P.; Pohl, R.; Pichová, I.; Votruba, I.; D{hacek over (z)}ubák, P.; Kone{hacek over (c)}ný, P.; Hajdúch, M.; Stray, K. M.; Wang, T.; Ray, A. S.; Feng, J. Y.; Birkus, G.; Cihlar, T.; Hocek, M. Synthesis and significant cytostatic activity of 7-hetaryl-7-deazaadenosines. J. Med. Chem. 2011, 54, 5498-5507).

These compounds exhibited nanomolar cytostatic and cytotoxic effect against a broad spectrum of leukemia and solid tumors. These compounds of formula A contained amino group in the position 6 of 7-deazapurine moiety, which can act as hydrogen donor in the formation of hydrogen bonds with target biological structures and thus mimics the bonding of natural nucleoside adenosine (Figure 1).

Weak cytostatic properties of 6-substituted 7-deazapurine ribonucleosides unsubstituted in position 7 were reported. (See Gerster, J. F.; Carpenter, B.; Robins, R. K.; Townsend, L. B. Pyrrolopyrimidine Nucleosides. I. The Synthesis of 4-Substituted 7-(-β-D-Ribofuranosyl) pyrrolo[2,3-d]pyrimidines from Tubercidin. J. Med. Chem. 1967, 10, 326-331). In the present document these compounds were used as reference compounds in SAR studies. Analogous 6-substituted 7-deazapurine ribonucleosides bearing cyano group in position 7 were prepared and displayed antiviral properties against HCV (See Varaprasad, C. V. N. S.; Ramasamy, K. S.; Girardet, J. -L.; Gunic, E.; Lai, V.; Zhong, W.; An, H.; Hong, Z., Bioorg. Chem. 2007, 35, 25-34). Antiviral activity of 6-methyl-7-deazapurine ribonucleoside was also recently reported (See Wu, R.; Smidansky, E. D.; Oh, H. S.; Takhampunya, R.; Padmanabhan, R.; Cameron, C. E.; Peterson, B. R. Synthesis of a 6-Methyl-7-deaza Analogue of Adenosine That Potently Inhibits Replication of Polio and Dengue Viruses. J. Med. Chem. 2010, 53, 7958-7966). This compound was used by the present inventors as reference compound in SAR studies. A series of 7-halogen substituted 6-methoxy-7-deazapurine ribonucleosides was prepared by Seela, but their biological properties were not tested (See Seela, F.; Ming, X. 7-Functionalized 7-deazapurine β-D and β-L-ribonucleosides related to tubercidin and 7-deazainosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D or β-L-ribofuranose. Tetrahedron 2007, 63, 9850-9861; Zhang, L.; Zhang, Y.; Li, X.; Zhang, L. Study on the Synthesis and PKA-I Binding Activities of 5-Alkynyl Tubercidin Analogues. Bioorg. Med. Chem. 2002, 10, 907-912). 5-iodo-4-methoxy-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine was used by the present inventors either as a starting material or as a reference compound is SAR studies.